(1) Field of the Invention
The present invention generally relates to genetic causes of disease. More specifically, the invention provides compositions and methods relating to a newly identified intestinal folate transporter and the cause of hereditary folate malabsorption.
(2) Description of the Related Art
Folates are essential cofactors required for the provision of one-carbon moieties in key biosynthetic and epigenetic processes (Stover, 2004). Folate deficiency is prevalent in under-developed countries and, even in the western world, subtle deficiency is a public health problem most notable in its association with neural tube defects in the developing embryo (Eichholzer et al., 2006). Mammals cannot synthesize folates; hence, dietary sources must meet metabolic needs necessitating an efficient intestinal absorptive mechanism. Absorption of folates occurs primarily in the duodenum and upper jejunum and involves a carrier-mediated process with a low-pH optimum that operates efficiently within the acidic microclimate of the intestinal surface in this region (Selhub and Rosenberg, 1981; Mason and Rosenberg, 1994; McEwan et al., 1990). The specificity and other properties of this process have been well established and similar folate transport activities with a low-pH optimum have been identified in other normal tissues and in human solid tumor cell lines (Horne, 1993; Zhao et al., 2004). Despite the prevalence and importance of this process, a folate transport protein with a low-pH optimum has not been identified.
There are two known, highly specific, mammalian folate transporters. Their properties were the subject of a recent review (Matherly and Goldman, 2003). The reduced folate carrier (SLC19A1) is a facilitative transporter with the characteristics of an anion exchanger. There are two GPI-linked folate receptors, high-affinity binding proteins that mediate cellular uptake by an endocytic mechanism. Folate receptor expression in small intestine is negligible. While the reduced folate carrier is expressed on the brush border membrane of intestinal cells, this transporter has a neutral pH optimum and a specificity profile that differs substantially from that observed in intestinal folate absorption and transport into intestinal cells and cells of other tissue origin at low pH (Selhub and Rosenberg, 1981; Mason and Rosenberg, 1994; Wang et al., 2004). Further, when reduced folate carrier function is lost due to deletion, mutation, or loss of expression of the gene, the low-pH folate transport activity remains intact (Zhao et al., 2004; Zhao et al., 2005b; Wang et al., 2005).
Hereditary folate malabsorption (HFM) (OMIM 229050) is a rare autosomal recessive disorder caused by impaired intestinal folate absorption with folate deficiency characterized by anemia, hypoimmunoglobulinemia with recurrent infections, such as Pneumocystis carinii pneumonitis, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or mental retardation emerge at some point in early childhood and have been attributed to impaired transport of folates into the central nervous system (Geller et al., 2002). When this disorder is diagnosed early, signs and symptoms of HFM can be obviated by parental administration of folates or with higher doses of folates by the oral route (Geller et al., 2002; Poncz and Cohen, 1996). If untreated, the disease is fatal and, if treatment is delayed, the neurological deficits can become permanent (Corbeel et al., 1985; Jebnoun et al., 2001). Hence, it is important that physicians are aware of this disorder and establish a diagnosis and institute treatment as early as possible in infancy. The clinical characteristics of HFM and its treatment were the subject of a recent comprehensive review (Geller et al., 2002).
Based on the above, it would be desirable to identify the molecular basis for HFM. The present invention addresses that need.